JP2011160994A - Bioabsorbable self-adhesive adhesion preventive material - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an effective and convenient adhesion preventive material required in a surgical field. <P>SOLUTION: The bioabsorbable adhesion preventive material includes an adhesive functional group on one side only of a sheet-like base material made of a bioabsorbable material. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a bioabsorbable self-adhesive anti-adhesion material having self-adhesive properties that is effective in preventing post-surgical biological tissue adhesion.

  In surgery in the surgical field, adhesion of living tissue that occurs after surgery is a major problem. For example, serious diseases such as endometriosis and acute intestinal obstruction occur due to adhesion of living tissue. In order to prevent adhesion of living tissues, composite films made of sodium hyaluronate and carboxymethyl cellulose and oxidized cellulose sheets have been clinically applied, but their anti-adhesion effect is not sufficient and their effectiveness is also satisfied by surgeons. Not as expensive as you get.

  Therefore, many studies have been made with the goal of developing effective anti-adhesion materials. However, at present, no satisfactory results have been obtained.

  In recent years, it has been reported that fibrin glue can be an effective anti-adhesive material. However, since fibrin glue is made from serum fibrinogen obtained from human plasma or bovine-derived thrombin, there is a risk of infection. Such problems are also great.

  As an ideal anti-adhesive material, after opening the packaged product in a surgical operation, it is immediately pressed against the living tissue where moisture remains, and it adheres to the living tissue without being fixed with sutures, preventing adhesion. It is a material that demonstrates its effects. However, even today, where advanced medical technology is born one after another, such materials do not exist.

  The reason is considered that there is a serious problem in the period until the material is absorbed into the body and the fixing method of the material on the soft tissue. In other words, if the material is absorbed within a short period of a few days or less, the healing of the damaged part has not yet progressed and adhesion is likely to occur, and conversely the material will take several months to decompose and absorb the material. Scar tissue forms around and causes adhesions from that site. Therefore, it is necessary that the material be bioabsorbed after a sufficient period of time for healing of the damaged part and within a period of time that does not cause adhesion.

  Examples of the method for fixing the material on the living tissue include a method for fixing by suturing with a suture thread and a method for fixing by self-adhesiveness of the material. However, in the former, even if an absorbable suture is used, there is a problem that adhesion occurs due to the suture that is a foreign substance, and in the latter, sufficient adhesion cannot be obtained. There is.

  The anti-adhesion materials currently used in the medical field are all too fast to be absorbed by the body, difficult to fix the material to the living tissue, and the form changes significantly when absorbed, making it extremely difficult to handle. In other words, a complicated preliminary operation is required before affixing on a living tissue. Accordingly, as described above, a bioabsorbable anti-adhesion material having self-adhesive properties that can be easily applied to a living tissue or an injured part thereof without using a suture or the like and that can provide a sufficient anti-adhesion effect. Development is anxious.

  Moreover, as a material having self-adhesiveness, a material in which a functional group that chemically reacts with the surface of a living tissue is introduced on the material surface has been reported (for example, see Patent Documents 1 and 2).

  In Patent Document 1, a compound containing a selective functional group of biological tissue and a substrate-reactive functional group different from that is used as a binder. Therefore, a complicated pre-operation is required before applying the anti-adhesion film to a living tissue. Moreover, in patent document 2, the medical material which consists of a bioabsorbable polymer which has an aldehyde group is disclosed. However, in Patent Document 2, aldehyde groups are introduced on both sides of the film, and no study has been made on introducing functional groups only on one side. Since the medical material described in Patent Document 2 has an aldehyde group on both sides, the other side that does not require adhesion prevention is likely to adhere to the adjacent living tissue, so it should be used as an adhesion prevention material. I can't.

Patent No. 4027445 JP 11-33104 A

  An object of the present invention is to provide an effective and easy-to-use self-adhesion type anti-adhesion material required in the surgical field.

  As a result of repeated research to solve these problems, adhesive functional groups that react rapidly with amino groups present on the surface of soft tissues of living bodies are introduced only on one surface of a sheet-like substrate made of a bioabsorbable material. Thus, the present inventors have found a material that can be quickly bonded to a living tissue by simply pressing the surface against the living tissue surface without using any other auxiliary material.

That is, the present invention provides the following bioabsorbable self-adhesive adhesion preventing material and a method for producing the material.
Item 1. A bioabsorbable self-adhesive anti-adhesion material having an adhesive functional group only on one side of a sheet-like substrate made of a bioabsorbable material.
Item 2. Item 2. The bioabsorbable self-adhesive anti-adhesion material according to Item 1, wherein the adhesive functional group is an aldehyde group.
Item 3. Item 3. The bioabsorbable self-adhesive anti-adhesive material according to Item 1 or 2, wherein the bioabsorbable material is at least one selected from the group consisting of gelatin, collagen, hyaluronic acid, chitosan, and a synthetic polypeptide.
Item 4. Item 4. The bioabsorbable self-adhesive adhesion-preventing material according to any one of Items 1 to 3, wherein the amount of the adhesive functional group present on the substrate is 0.001 to ² μmol / cm ² .
Item 5. One surface of a sheet-like substrate made of a bioabsorbable material prepared by a solution casting method or a casting method is treated with a solution containing a compound having an adhesive functional group, and the adhesive functional group is applied only to one surface of the substrate. Item 5. A method for producing a bioabsorbable self-adhesive anti-adhesion material according to any one of Items 1 to 4, which is introduced.
Item 6. A sheet-like substrate made of a bioabsorbable material prepared by a solution casting method or a casting method is bonded to only one surface of the substrate without peeling off from the support used in the solution casting method or the casting method. Item 6. A method for producing a bioabsorbable self-adhesive anti-adhesion material according to Item 5, wherein a group is introduced.
Item 7. Covering one side of a sheet-like base material made of a bioabsorbable material produced by a solution casting method or a casting method with a liquid-impermeable membrane and introducing an adhesive functional group only on the opposite side of the covered side Item 6. A method for producing a bioabsorbable self-adhesive anti-adhesion material according to Item 5.
Item 8. One side of a sheet-like base material made of a bioabsorbable material is irradiated with ultraviolet rays having a wavelength of 250 to 260 nm at 1 to 6 J / cm ² to crosslink the adhesive functional group introduction surface, and then the opposite side of the surface is 250 to 260 nm. The term which bridge | crosslinks by irradiating 2-4 J / cm < ² > of the ultraviolet-ray of the wavelength of this, or heat-treats the sheet-like base material which consists of bioabsorbable materials at 80-200 degreeC for 5 minutes-48 hours. The manufacturing method of the bioabsorbable self-adhesion type | mold adhesion prevention material in any one of 5-7.
Item 9. Item 9. The method for producing a bioabsorbable self-adhesive anti-adhesion material according to any one of Items 5 to 8, wherein the solvent of the solution containing the compound having an adhesive functional group is a water-containing organic solvent.
Item 10. Item 10. The living body according to Item 9, wherein the water-containing organic solvent is a mixed solvent of at least one organic solvent selected from alcohols, ketones, and esters and water, and the amount of the organic solvent is 70 to 99 V / V%. A method for producing an absorbent self-adhesive anti-adhesion material.
Item 11. Item 11. The method for producing a bioabsorbable self-adhesive adhesion preventing material according to any one of Items 5 to 10, wherein the compound containing an adhesive functional group is glutaraldehyde and the bioabsorbable material is gelatin.

  The bioabsorbable self-adhesive anti-adhesion material of the present invention has an adhesive functional group only on one side of a sheet-like base material made of a bioabsorbable material, so that the bioabsorbable self-adhesive anti-adhesion material exists on the surface of the living tissue simply by pressing it onto the surface of the living tissue. It reacts quickly with the amino group, and can adhere to the living tissue without using any other auxiliary material, and can prevent adhesion of the living tissue after surgery. For example, it is possible to prevent endometriosis that occurs after surgery in the field of obstetrics and gynecology and causes infertility, and adhesion of intestinal tissue that frequently occurs after surgery in the gastrointestinal surgery field, causing intestinal obstruction. Medical and social effects are enormous.

It is a figure which shows the density | concentration of a glutaraldehyde solution, and the amount of aldehyde introduction | transduction. It is a figure which shows the moisture content of a liquid mixture, and the amount of aldehyde introduction | transduction.

1. BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a bioabsorbable adhesion preventing material having an adhesive functional group only on one side of a sheet-like substrate made of a bioabsorbable material. Hereinafter, the bioabsorbable adhesion preventing material of the present invention will be described in detail.

1-1. Sheet-like substrate made of bioabsorbable material The substrate made of bioabsorbable material used in the present invention has a sheet-like shape. In the present invention, the sheet-like shape means, for example, a film-like shape or a ribbon-like shape. Is included.

  The base material composed of the bioabsorbable material used in the present invention is preferably a naturally derived material with proven biosafety, such as gelatin, collagen, hyaluronic acid, chitin, chitosan, and synthetic polypeptide, A cellulose derivative etc. can be mentioned. Among these, gelatin is preferable from the viewpoint of controlling the strength of the material and the bioabsorption rate.

  The thickness of the base material made of the bioabsorbable material is not particularly limited, and can be determined as appropriate according to the relationship such as the site to be used, desired strength, bioabsorption rate, and operability. Therefore, although not particularly limited, for example, it is preferably about 5 to 500 μm, and more preferably about 10 to 100 μm. Although it varies depending on the degree of cross-linking, the time for degradation in vivo can be changed between several hours to several months by controlling the thickness.

  The sheet-like substrate made of a bioabsorbable material is preferably crosslinked. The crosslinking method will be described later.

1-2. Adhesive functional group The adhesive functional group is not particularly limited, and examples thereof include an aldehyde group and a succinimide group. Since a large amount of amino groups are present on the surface of the living tissue to which the bioabsorbable anti-adhesion material of the present invention is applied, it can react quickly at room temperature in the presence of the amino groups and moisture, and the presence of water Aldehyde groups are preferred because the bioabsorbable adhesion-preventing material can be stably stored even underneath. In addition, an aldehyde group is preferable because it can easily react with an amino group at a temperature in the vicinity of 37 ° C. which is a temperature in the living body.

The amount of adhesive functional groups present on the surface of the substrate is preferably 0.001~2μmol / cm ^2, further preferably 0.001~0.2μmol / cm ^2. If the amount of the adhesive functional group present on the surface of the substrate exceeds the above range, the adhesion to the tissue may be too strong and may cause harm to the tissue. If it is too low, it tends to peel off, and the adhesion prevention effect may be reduced.

  The amount of the adhesive functional group present on the surface of the substrate can be measured with a spectrophotometer using an Elman reagent after reaction with cysteamine hydrochloride.

  The method for introducing the adhesive functional group will be described later.

  When the bioabsorbable anti-adhesion material of the present invention is embedded in a living body, it can quickly adhere to a portion where it is desired to prevent adhesion, and it can be hydrolyzed within a desired period (for example, about several weeks). It can be absorbed into the living body and disappear.

2. Method for Producing Bioabsorbable Adhesion Prevention Material The method for producing the bioabsorbable antiadhesive material of the present invention comprises a compound having an adhesive functional group on one side of a sheet-like substrate made of a bioabsorbable material prepared by a solution casting method. And an adhesive functional group is introduced only on one side of the substrate.

2-1. Manufacturing method of sheet-like substrate made of bioabsorbable material A sheet-like substrate made of a bioabsorbable material is produced by a solution casting method or a casting method. It is preferable that a bioabsorbable polymer as a raw material is dissolved in a solvent, and a sheet-like substrate is produced from the solution (hereinafter also referred to as a bioabsorbable material solution) by a solution casting method or a casting method. Although the density | concentration of a bioabsorbable material solution is not specifically limited, It is preferable that it is about 0.1 to 30 weight%, and it is preferable that it is about 1 to 20 weight%. It exists in this range, since the viscosity of a solution becomes the range which is easy to handle and manufacture can be made easy. The bioabsorbable material is as described above.

Here, the solution casting method is a method in which a bioabsorbable material solution is stretched into a sheet and the solvent is separated by a known method. The solvent used in the solution casting method is not particularly limited as long as it can dissolve the bioabsorbable material, and examples thereof include water, PBS, Tris buffer, and the like. Among these, water is preferable from the viewpoint of safety and handleability.
The solution is cast by extruding the solution from a die having a certain width onto a support such as an aluminum foil, a resin film, a metal drum, or a steel belt placed on a balance table. It is also possible to produce a sheet-like substrate having a uniform thickness by applying the solution by spraying, brushing, roll, spin coating or the like and drying.

The drying time in the solution casting method is not particularly limited because it depends on the type of bioabsorbable material, the solution concentration, and the like. For example, it is preferable to dry at 10 to 100 ° C. for 20 to 50 hours.
The casting method is a method in which the bioabsorbable material solution is cast on a support such as an aluminum foil placed on a balance table and air-dried as it is, or the bioabsorbable material is placed in a mold. In this method, the material solution is poured and air-dried as it is. When the casting method is used, a bioabsorbable material solution is poured into a mold and air-dried to obtain a film. Therefore, glutaraldehyde is added onto the film in the mold without removing the film from the mold. There is an excellent effect that the material of the present invention can be obtained by pouring the organic solvent and water mixed solution contained therein and crosslinking only one side.

2-2. The sheet-like substrate made of the bioabsorbable material obtained by crosslinking treatment is preferably subjected to crosslinking treatment. Crosslinking may be performed on the entire substrate, or a crosslinking treatment may be performed on a part of the substrate (for example, one side of the substrate).

  The crosslinking method is not particularly limited, and examples thereof include thermal dehydration crosslinking, ultraviolet crosslinking, and the like. In the case of a substrate made of gelatin, glutaraldehyde crosslinking can also be performed.

  In the present invention, it is preferable to provide a gradient of the degree of crosslinking in the cross-sectional direction of the substrate. As a method for giving a gradient of the degree of cross-linking in the cross-sectional direction of the substrate, a method of irradiating ultraviolet rays from only one side of the substrate, a method of irradiating ultraviolet rays from one side of the substrate, and then irradiating ultraviolet rays from the other surface, etc. Can be mentioned. When heat crosslinking or glutaraldehyde crosslinking is carried out by a usual method, crosslinking is carried out almost uniformly in the cross-sectional direction of the substrate, which is not always desirable for preventing adhesion.

The conditions of the ultraviolet crosslinking is not particularly limited, for example, preferably be crosslinked by irradiation with ultraviolet rays having a wavelength of 250~260nm at 1~6J / cm ^2, was irradiated with 2~4J / cm ² cross It is preferable to do. Crosslinking within this range is preferable because an appropriate bioabsorption rate can be obtained. When ultraviolet rays are irradiated from the opposite surface after ultraviolet irradiation from the surface of the substrate (adhesive functional group-introduced surface), the conditions may be the same or different on the opposite surface.

  The conditions for heat crosslinking are not particularly limited, but for example, heat treatment is preferably performed at 80 to 200 ° C. for 5 to 48 hours, more preferably 100 to 130 ° C. for 12 to 24 hours.

  The conditions for glutaraldehyde crosslinking are not particularly limited. For example, it is performed by immersing in a 0.01 to 10 W / W% glutaraldehyde solution (solvent: ethanol-water mixed solution) for 0.5 to 3 hours. be able to.

2-3. Introduction of adhesive functional group Adhesive functional groups are introduced only on one side of the sheet-like substrate subjected to the crosslinking treatment. When the above crosslinking treatment is carried out by heat crosslinking or glutaraldehyde crosslinking, since the crosslinking is uniformly applied to the entire substrate, an adhesive functional group can be introduced only on one of the surfaces. When the crosslinking treatment is performed by irradiating ultraviolet rays from one side of the sheet-like substrate, it is preferable to introduce an adhesive functional group to the surface on the ultraviolet irradiation side having a high degree of crosslinking.

  In the bioabsorbable adhesion preventing material of the present invention, it is necessary to introduce an adhesive functional group only on one side, and if the adhesive functional group is introduced on the other side, the effect of the present invention cannot be fully exhibited. It is not preferable. It is known that a gelatin film is cross-linked with glutaraldehyde. However, when the degree of cross-linking is low, the surface of the film does not have sufficient self-adhesiveness. A higher glutaraldehyde concentration is required to provide sufficient self-adhesion. Although such double-sided self-adhesive films have actually been reported in academic papers (Matsuda et al., J Biomed Mater Res, 1999, 45 (1), 20-27), such double-sided self-adhesive properties A film is not suitable for the purpose of the present invention because the opposite surface of the tissue adhesive surface may react with a biological component.

  As a method for introducing an adhesive functional group only on one side of the substrate, for example, a solution containing a compound having an adhesive functional group on the opposite side of the surface on which the adhesive functional group is introduced (hereinafter referred to as the adhesive functional group introduction surface) is impregnated. By treating the adhesive functional group introduction surface under such conditions, the adhesive functional group can be introduced only on one side of the substrate. In general, a reaction medium having a low affinity with the substrate is selected so that the reaction is limited to the vicinity of the introduction surface.

  On the other hand, the purpose can be achieved only by covering the surface opposite the adhesive functional group introduction surface. As the method, for example, a method in which a sheet-like base material is processed without being peeled from a support (for example, aluminum foil, formwork, etc.) used in the solution casting method, or the side opposite to the adhesive functional group introduction surface is used. The method of processing after covering the surface with a liquid-impermeable film, a plastic plate, an adhesive tape, etc., the method of processing with the sheet-like substrate placed in the mold used in the casting method, etc. .

  Examples of the liquid-impermeable film include a polyethylene film and a silicone sheet.

  When the surface opposite to the adhesive functional group introduction surface of the sheet-like substrate made of the bioabsorbable material used in the present invention is covered, the side surface is not covered, but the sheet-like substrate of the present invention is not covered. Since the film thickness is very thin, even if an adhesive functional group is introduced into the side surface, the adhesion between the introduction portion and the tissue does not become a problem.

  Moreover, depending on the site | part etc. which use the bioabsorbable adhesion prevention material of this invention, an adhesive functional group can also be introduce | transduced limited only to a part of adhesive functional group introduction | transduction surface of a sheet-like base material. In that case, what is necessary is just to cover and process a part of adhesive functional group introduction | transduction surface of a sheet-like base material by the above-mentioned method.

  The compound having an adhesive functional group varies depending on the type of the adhesive functional group to be introduced, but when the adhesive functional group is an aldehyde group, examples include glutaraldehyde and formaldehyde. Further, when the adhesive functional group is a succinimide group, N, N′-disuccinimidyl carbonate, phthalimidyl alcohol, succinimidyl alcohol and the like can be exemplified.

  The solvent used in the solution containing the compound having an adhesive functional group is not particularly limited. For example, alcohols such as n-propanol, ethanol, and methanol; ketones such as acetone, ethyl acetate, butyl acetate, and the like Ester, water, or a mixed solvent thereof. Among these, a water-containing organic solvent obtained by mixing an organic solvent and water is preferable from the viewpoint of handleability.

  In the present invention, it is preferable to use a mixed solvent of an organic solvent and water. By using a mixed solvent of an organic solvent and water, a solution containing a compound having an adhesive functional group can penetrate only to the vicinity of the surface of the substrate, and as a result, the adhesive functional group can be introduced only on one side of the substrate. This is preferable because it is possible.

  The amount of the organic solvent contained in the water-containing organic solvent is preferably 70 to 99 V / V%, and more preferably 80 to 95 V / V%. It is preferable that the organic solvent ratio is within the above range because the water-containing organic solvent does not penetrate into the bioabsorbable material, and as a result, the functional group is introduced only near the surface.

  The concentration of the solution containing the compound having an adhesive functional group is preferably 0.01 to 10% by weight, and more preferably 0.02 to 5% by weight. When the concentration is within the above range, the introduction of the functional group is preferable because it is limited to the target surface and the vicinity of the surface.

  The treatment time with the solution containing the compound having an adhesive functional group is preferably 0.5 to 24 hours, more preferably 0.5 to 3 hours, and the reaction temperature is 4 to 60 ° C. Preferably, it is 15-25 degreeC.

  In the present invention, among the above, the adhesive functional group is preferably an aldehyde group, and the compound having the adhesive functional group is preferably glutaraldehyde. Some aldehyde groups in this glutaraldehyde react with amino groups on the surface of the sheet-like substrate, and other unreacted aldehyde groups can react with amino groups on the tissue surface. It can be bonded quickly.

  In the present invention, the adhesive functional group is once introduced into both the adhesive functional group-introduced surface and the opposite surface of the sheet-like base material, and then subjected to a specific treatment on the opposite surface. It can be extinguished.

  As a treatment method in that case, for example, a method of bringing an oxidizing agent such as hydrogen peroxide into contact can be exemplified.

  The bioabsorbable adhesion preventing material of the present invention is adhered to the soft tissue surface by wiping as much water as possible on the soft tissue surface before placing the bioabsorbable adhesion preventing material on the soft tissue. At this time, care should be taken not to leave air at the interface as much as possible.

Adhesion between soft tissue and material proceeds by simply pressing the material lightly for a while. The pressure at that time is about 20 to 40 g / cm ² . The time for pressing depends on the surface condition of the soft tissue, but is about 10 to 60 seconds, and even if it is about 20 to 40 seconds, it is sufficiently bonded.

  EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated, this invention is not limited to these Examples.

Example 1
Gelatin (manufactured by Nitta Gelatin Co., Ltd., # 250) was dissolved in water to prepare a 2.5 wt% aqueous solution, which was cast on an aluminum foil placed on a balance table, 25 ° C., 16 The resultant was air-dried for a time to obtain a gelatin film having a thickness of about 30 μm. Ultraviolet rays are applied to one side (the gelatin side, not the aluminum foil side) of the gelatin film obtained using a sterilizing ultraviolet lamp (manufactured by Toshiba Corporation, GL-15, wavelength: 254 nm, 15 W). Irradiated cm ² .

  Subsequently, the gelatin film was put in a glutaraldehyde solution (solvent: n-propanol, glutaraldehyde concentration: 5% by weight) while adhering to the aluminum foil without peeling the film from the aluminum foil, and reacted at 60 ° C. for 2 hours. It was. Thereafter, the gelatin film fixed to the aluminum foil was taken out, washed with n-propanol, and then air-dried at 25 ° C. for 1 hour to peel off the aluminum foil.

The amount of aldehyde groups present on the surface of the substrate was 0.001 μmol / cm ² . The amount of aldehyde groups was measured with a spectrophotometer using an Elman reagent after reaction with cysteamine hydrochloride.

<Test 1>
The adhesion prevention effect in the case of the film obtained in Example 1 sterilized with ethylene oxide gas, Sepra film (registered trademark, manufactured by Kaken Pharmaceutical Co., Ltd.) and no film was evaluated by the following method.
(Evaluation of adhesion prevention effect)
The rat abdomen was incised under anesthesia, and the serosa with a diameter of 15 mm was loosely damaged so as to cause adhesion between the anterior cecum wall and abdominal wall. The abdomen was sutured with the film obtained in Example 1 and Sepura film (registered trademark) sterilized with ethylene oxide gas (each size being 2 cm × 2 cm) or without attaching the film to the wound part. Also, after 2 weeks, the abdomen was opened and the presence or absence of adhesion was observed to evaluate the adhesion prevention effect. Each test was evaluated in an 8 rat model. The results are shown in Table 1.

  Here, the strong adhesion means an adhesion that is 75% or more of the treatment area and requires 50% or more of sharp peeling, and “medium adhesion” means 50% of the treatment area. It means the following adhesions that require exfoliation with force.

Example 2
Gelatin (manufactured by Nitta Gelatin Co., Ltd., # 250) was dissolved in water to prepare a 2.5 wt% aqueous solution, which was cast into a petri dish made of polystyrene (9φ × 1.5 cm), 25 ° C., It was dried for 48 hours to produce a gelatin film having a thickness of about 30 μm. Without peeling off the film from the petri dish surface, the surface of the gelatin film was irradiated with 2.59 J / cm ² of 15 W ultraviolet light (wavelength: 254 nm) using the same sterilizing ultraviolet lamp as in Example 1.

  Subsequently, 3 mL of a glutaraldehyde solution (medium: water-ethanol (ethanol / water = 95/5), glutaraldehyde concentration: 0.025 wt%) was placed on a petri dish with the film fixed, and the mixture was kept at 25 ° C. for 1 hour. Reacted. The glutaraldehyde solution was removed from the petri dish, washed with a water-ethanol solvent (ethanol / water = 95/5), dried at 25 ° C. for 16 hours, and the film was peeled off from the petri dish.

Thereafter, the surface of the film that had been fixed to the petri dish was irradiated with 2.59 J / cm ² of 15 W ultraviolet light (wavelength: 254 nm).

The amount of aldehyde groups present in the substrate was 0.005 μmol / cm ² . The amount of aldehyde groups was measured in the same manner as in Example 1.

<Test 2>
The anti-adhesion effect for the film obtained in Example 2, Sepra film (registered trademark, manufactured by Kaken Pharmaceutical Co., Ltd.), and no film was evaluated by the following methods.
(Evaluation of adhesion prevention effect)
The abdomen of the dog was incised by anesthesia, and the serosa 5 × 5 cm 10 cm from the ileocecal part to the mouth side was gently scraped off with a sandpaper so as to cause adhesion. After hemostasis, paste the film obtained in Example 2 sterilized with ethylene oxide gas and Sepra film (registered trademark, manufactured by Kaken Pharmaceutical Co., Ltd.) sterilized with ethylene oxide gas (each size is 6 × 6 cm) Then, the gauze placed on the film was pressed by hand for 30 seconds. Thereafter, the abdomen was sutured. In other test dog models, the abdomen was sutured without attaching a film.

  After 3 weeks, the abdomen was opened and the presence or absence of adhesion was observed to evaluate the adhesion prevention effect. The results are as follows. Each test was evaluated in 8 dog models. The results are shown in Table 2.

  Here, the strong adhesion means an adhesion that is 75% or more of the treatment area and requires 50% or more of sharp peeling, and “medium adhesion” means 50% of the treatment area. It means the following adhesions that require exfoliation with force.

Example 3
As in Example 2, gelatin was dissolved in water to prepare a 2.5 wt% aqueous solution, which was cast on a petri dish (9φ × 1.5 cm), air-dried at 25 ° C. for 16 hours, A gelatin film of about 30 μm was prepared. The gelatin film was irradiated with 2.59 J / cm ² of 15 W ultraviolet light (wavelength: 254 nm) using the same sterilizing ultraviolet lamp as in Example 1 without peeling off the gelatin film from the petri dish surface.

  Subsequently, 3 mL of an ethanol solution of glutaraldehyde having different glutaraldehyde concentration and water content (glutaraldehyde concentration: 0.5 to 3% by weight, water content: 6 to 25% by weight) is placed on the petri dish to which the film is fixed. The reaction was carried out at 1 ° C. for 1 hour.

After washing with an ethanol solution containing the same amount of water as the reaction solution and drying, the gelatin film was peeled off from the petri dish and taken out. Subsequently, the surface of the gelatin film that was in contact with the petri dish surface was irradiated with 2.59 J / cm ² of 15 W ultraviolet light.

  Here, the result of the aldehyde group amount of the gelatin film when the glutaraldehyde concentration is changed (water content: 10% by weight) is shown in FIG. 1, and when the water content is changed (glutaraldehyde concentration: 2% by weight). The result of the aldehyde group amount of the gelatin film is shown in FIG.

In FIG. 1 and FIG. 2, “adhesion surface” refers to the surface that adheres to the obtained living body, that is, the surface of the gelatin film that has been in contact with the ethanol solution of glutaraldehyde. The “opposite surface” refers to the surface that was in contact with the petri dish surface when the gelatin film was treated with an ethanol solution of glutaraldehyde.
<Test 3>
The following adhesion evaluation was performed using the film obtained in Example 3.
(Adhesion evaluation method)
The adhesion due to the reaction between the aldehyde group of the obtained film and the amino group of the tissue was measured using a chicken thigh meat and a chitosan film as a biological tissue model. After adhering them to the various films obtained in Example 3, they were placed in PBS (phosphate buffered saline) at 37 ° C. and gently stirred (stirring speed in the case of chicken leg meat: 60 rpm) Table 3 below shows the observation results when the stirring speed in the case of a chitosan film was 100 rpm. The pressing for adhesion is only to place a finger lightly (about 30 g / cm ² ). The chitosan film was pressed for about 30 seconds after bonding, and the chicken thigh was not pressed after bonding.

  In Table 3, GA concentration indicates the concentration of an ethanol solution of glutaraldehyde.

The evaluation criteria are as follows.
(Bird thigh)
X: Completely peeled off.

  Δ: Half peeled.

○: Adhered after 2 hours.
(Chitosan film)
X: Completely peeled off.

  ○: It remains adhered after 30 minutes.

Example 4
PI5 gelatin (for photographs) manufactured by Nippi Co., Ltd. was dissolved in distilled water to prepare a 2.65% by weight gelatin aqueous solution. 20 μL of a 25 wt% glutaraldehyde aqueous solution was mixed with 10 mL of gelatin aqueous solution (for one petri dish), poured into a petri dish, and air-dried with a clean bench to prepare a film with a thickness of 30 μm. Thereafter, a solution obtained by diluting a 30% aqueous hydrogen peroxide solution with ethanol (4% H ₂ O ₂ ) was placed in a 3 mL petri dish and placed at 25 ° C. for 1 hour. One surface in contact with the H ₂ O ₂ is eliminated aldehyde group, there will be an aldehyde group only dish surface not in contact with the H ₂ O _2. After washing with ethanol and drying, a film having an aldehyde group only on one side of the film was produced.

About the obtained film, it evaluated by the method similar to Example 3 about whether it adhere | attaches with a chitosan film. As a result, the surface treated with H ₂ O ₂ peeled off within 30 minutes, whereas the petri dish contact surface where aldehyde groups were present did not peel off.

Claims (11)

  A bioabsorbable self-adhesive anti-adhesion material having an adhesive functional group only on one side of a sheet-like substrate made of a bioabsorbable material.   The bioabsorbable self-adhesive anti-adhesion material according to claim 1, wherein the adhesive functional group is an aldehyde group.   The bioabsorbable self-adhesive material according to claim 1 or 2, wherein the bioabsorbable material is at least one selected from the group consisting of gelatin, collagen, hyaluronic acid, chitosan, and a synthetic polypeptide. The bioabsorbable self-adhesive anti-adhesion material according to any one of claims 1 to 3, wherein the amount of the adhesive functional group present on the substrate is 0.001 to ² µmol / cm ² .   One surface of a sheet-like substrate made of a bioabsorbable material prepared by a solution casting method or a casting method is treated with a solution containing a compound having an adhesive functional group, and the adhesive functional group is applied only to one surface of the substrate. The method for producing a bioabsorbable self-adhesive anti-adhesion material according to any one of claims 1 to 4, which is introduced.   A sheet-like substrate made of a bioabsorbable material prepared by a solution casting method or a casting method is bonded to only one surface of the substrate without peeling off from the support used in the solution casting method or the casting method. 6. The method for producing a bioabsorbable self-adhesive anti-adhesion material according to claim 5, wherein a group is introduced.   Covering one side of a sheet-like base material made of a bioabsorbable material produced by a solution casting method or a casting method with a liquid-impermeable membrane and introducing an adhesive functional group only on the opposite side of the covered side The method for producing a bioabsorbable self-adhesive anti-adhesion material according to claim 5. One side of a sheet-like base material made of a bioabsorbable material is irradiated with ultraviolet rays having a wavelength of 250 to 260 nm at 1 to 6 J / cm ² to crosslink the adhesive functional group introduction surface, and then the opposite side of the surface is 250 to 260 nm. Claims to crosslink by irradiating ² to 4 J / cm ² of ultraviolet rays having a wavelength of, or heat treating a sheet-like substrate made of a bioabsorbable material at 80 to 200 ° C. for 5 minutes to 48 hours Item 8. A method for producing a bioabsorbable self-adhesive anti-adhesion material according to any one of Items 5 to 7.   The method for producing a bioabsorbable self-adhesive anti-adhesion material according to any one of claims 5 to 8, wherein the solvent of the solution containing the compound having an adhesive functional group is a water-containing organic solvent. The water-containing organic solvent is a mixed solvent of at least one organic solvent selected from alcohols, ketones and esters and water, and the amount of the organic solvent is 70 to 99 V / V%. A method for producing a bioabsorbable self-adhesive anti-adhesion material   The method for producing a bioabsorbable self-adhesive anti-adhesion material according to any one of claims 5 to 10, wherein the compound containing an adhesive functional group is glutaraldehyde, and the bioabsorbable material is gelatin.

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